A variety of recent developments are responsible for an increase in the incidence and variety of fungal infections, including the intensive use of chemotherapy for bacterial infections, a wider use of catheterization, and an increase in the number of patients who are immune-suppressed due to organ transplantation and other medical procedures (cf., M. Rinaldi in Infectious Disease Clinics of North America Vol. 3, D. J. Drutz, Ed., B. Saunders Co., Philadelphia, 1989, p. 65). Many reports describe infections by fungi not previously recognized as human pathogens. In addition, the advent of AIDS has created a group of immuno-compromised patients who are predisposed to fungal infections with a unique pattern of infection. In this patient population, oral and esophageal Candida infections are prevalent and Cryptococcus has emerged as a major pathogen. As a result of these developments, the relative importance of the fungal pathogens has changed in recent years and there is an even greater need for effective antifungal agents.
Amphotericin B, a fungicidal agent of the polyene macrolide class, is effective against a number of fungal infections which prior to the availability of this drug were almost invariably fatal. However, amphotericin B is characterized by poor oral bioavailability and considerable mammalian toxicity, and is capable of causing a variety of untoward effects including anaphylaxis, thrombocytopenia, flushing, generalized pain, convulsions, chills, fever, phlebitis, headache, anemia, anorexia and decreased kidney function (M. W. DeGregorio, et. al., Amer. J. Med., 1982, 73:543-548). Nephrotoxicity is an especially significant problem and 80% of patients treated with amphotericin B experience impaired kidney function. Much of the current work in antifungal research is directed to attempting to reduce the toxicity of amphotericin B by altering its pharmacokinetic properties, for example, cf., PCT Patent Application No. WO 90/1873, published Mar. 8, 1990, for aerosol formulations. Efforts to reduce the toxicity of amphotericin B by chemical modification have been unsuccessful thus far (P. D. Hoeprich, et al., Ann. N.Y. Acad. Sci., 1988, 544:517). A recent survey also suggests that resistance to amphotericin B among species of Candida and Torulopsis is becoming a significant problem (W. G. Powderly, Amer. J. Med., 1988, 84:826-832).
Ketoconazole, the leading member of the azole class of antifungal compounds, is orally active and has been used clinically for many years. Ketoconozole and other azoles also suffer from several disadvantages. For example, they are fungistatic and not fungicidal, are inhibitors of the biosynthesis of testosterone, are hepatotoxins and are poorly absorbed into the cerebrospinal fluid. Resistance to azole antifungal agents has also been documented.
In view of the scarcity of agents currently available to the physician, there is an evident need for accelerated development of new, more effective and less toxic antifungal drugs, especially for treating systemic fungal infections.
The compounds of the present invention comprise novel benzodithiazole-1-oxides. 1,2,3-Benzodithiazole-2-oxide and 1,3,2-benzodithiazole-1,1-dioxides have been previously described; they are not, however, known as antifungal agents. For example, J. L. Ahle and W. C. Doyle, in U.S. Pat. No. 3,490,893, issued Jan. 20, 1970, disclose 3H-1,2,3-benzodithiazole-2-oxides which are useful for combating weeds in small grains. J. Uhlendorf et al., in German Offenlegungsschrift Number DE 3635696, published Apr. 28, 1988, disclose benzo-1,3-2-dithiazol-1,1-dioxides said to be useful as antiflammatory and antiallergy agents.
The synthesis of 5-methyl-1,3,2-benzodithiazoles, intermediates in the preparation of the novel 1,3,2-benzodithiazole-1-oxides of the present invention, has been reported in the literature ((C. H. Chen and B. A. Donatelli, J. Heterocyclic Chem., 1979, 16:183-185). These compounds were prepared as components of charge transfer salts, and are not known to have any biological activity.
G. Massimo, et al, II Farmaco, 1990, 45:439-446 describe biological studies on 1,2-benzisothiazole-3-ones and report antibacterial and antifungal activity for these compounds. None of the above references, however, disclose or suggest the novel compounds of the present invention.